Regulation of arterial phenotype by perivascular adipose tissue in cardiometabolic disease

心脏代谢疾病中血管周围脂肪组织对动脉表型的调节

• 批准号: 10231190
• 负责人: Lucy Liaw
• 金额: $ 50.93万
• 依托单位: MAINEHEALTH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10231190
• 关键词: Adipocytes; Adipose tissue; Affect; Anatomy; Apolipoprotein E; Atherosclerosis; Biology; Blood Vessels; Brown Fat; Cardiometabolic Disease; Cardiovascular Diseases; Cell physiology; Cells; Characteristics; Clinical; Coronary Artery Bypass; Country; Disease; Disease Progression; Disease susceptibility; Endocrine Glands; Endothelium; Environment; Fatty acid glycerol esters; Genes; Genetic; Goals; High Fat Diet; Human; In Vitro; Individual; Inflammation; Knockout Mice; Left; Light; Link; Mediator of activation protein; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolic stress; Modeling; Molecular; Mus; Myocardial Infarction; Obesity; Obesity Epidemic; Operative Surgical Procedures; Paracrine Communication; Pathologic; Patients; Phenotype; Play; Predisposition; Production; Proteins; Proteomics; Regulation; Role; Sampling; Signal Transduction; Sirtuins; Smooth Muscle Myocytes; Testing; Thoracic aorta; Tunica Adventitia; Vascular Diseases; Vasodilation; adipokines; athero susceptible; atherogenesis; base; cardiovascular health; cardiovascular risk factor; feeding; genetic approach; in vivo; mortality; mouse genetics; mouse model; notch protein; novel; paracrine; progenitor; proteomic signature; response

Cardiovascular diseases such as atherosclerosis are compounded in individuals who are obese, and metabolic disease and cardiovascular diseases are tightly linked. In part due to the obesity epidemic, cardiovascular disease remains the highest cause of mortality in our country. The goal of this project is to understand how adipose tissue directly surrounding blood vessels, perivascular adipose tissue (PVAT), regulates the vascular microenvironment. During obesity, PVAT expands and becomes dysfunctional, and we propose that these changes establish an atherosusceptible environment that promotes vascular disease. In preliminary studies, we have analyzed both human and mouse PVAT and found elevated levels of Notch signaling. This is true in human PVAT derived from patients with advanced vascular disease undergoing coronary artery bypass grafting surgery, as well as in mice fed a high fat diet. We hypothesize that constitutive Notch signaling in PVAT in conditions of obesity or high fat feeding leads to changes in Sirt proteins, which in turn affect the secretion of paracrine factors from PVAT to the vessel wall. Our approaches to test this hypothesis include an in-depth proteomic study of human PVAT derived from individuals with different stages of vascular disease, and corresponding analysis of PVAT in mouse models of atherogenesis. The aims of this project are: Specific Aim 1. Identify unique protein signatures of human and mouse PVAT that define atheroresistant versus atherosusceptible microenvironments. We will define novel targets in the PVAT secretome that regulate vascular cells under conditions of high fat diet and atherogenesis. Identified targets that potentially are protective or could aggravate vascular dysfunction will be tested directly for effects on vascular cells in vitro. Specific Aim 2. Determine how elevated Notch signaling in PVAT during obesity affects its phenotype and vascular disease. We will use a mouse genetic approach to alter Notch signaling in PVAT, and combine that with an ApoE null mouse on a high fat diet to study the effect on PVAT biology and atherogenesis. PVAT phenotype will be assessed based on identity as brown, beige, or white fat-like; and by assessment of adipokine production and inflammation. Unique Notch targets may be identified by cross-referencing changes in protein signatures identified in aim 1. Finally, PVAT adipocyte progenitors and their differentiation capacity will be characterized under different high fat diet conditions leading to atherosclerosis. Specific Aim 3. Evaluate the hypothesis that Notch regulation of Sirt genes during obesity contributes to changes in PVAT phenotype and its paracrine signaling activity to the vessel wall. We will utilize in vivo analysis using human PVAT derived from coronary artery bypass graft surgery, mouse models of obesity, and ex vivo studies with isolated PVAT from mice differing in Notch activity and metabolic state.

心血管疾病，如动脉粥样硬化，在肥胖和新陈代谢的个体中是复杂的。 疾病和心血管疾病是紧密相连的。部分原因是肥胖流行，心血管疾病 在我国，疾病仍然是最高的死亡原因。这个项目的目标是了解如何 直接围绕血管的脂肪组织，血管周围脂肪组织(PVAT)，调节血管 微环境。在肥胖期间，PVAT扩张并变得功能失调，我们认为这些 变化建立了促进血管疾病的易受动脉粥样硬化影响的环境。在初步研究中， 我们分析了人和小鼠的PVAT，发现Notch信号水平升高。这在中国是正确的 人PVAT来源于接受冠状动脉搭桥术的晚期血管疾病患者 移植手术，以及在喂食高脂饮食的小鼠身上。我们假设构成凹槽的信号在 在肥胖或高脂肪喂养的情况下，PVAT会导致Sirt蛋白的变化，进而影响 PVAT向管壁分泌旁分泌因子。我们测试这一假设的方法包括 血管疾病不同阶段人PVAT蛋白质组学的深入研究 并对PVAT在小鼠动脉粥样硬化模型中的表达进行了相应分析。该项目的目标是： 具体目的1.确定定义抗动脉粥样硬化的人和小鼠PVAT的独特蛋白质特征 与易受动脉粥样硬化影响的微环境相比。我们将在PVAT分泌组中定义新的靶点 高脂饮食和动脉粥样硬化条件下的血管细胞。确定的目标可能是 保护或可能加重血管功能障碍将直接在体外测试对血管细胞的影响。 明确目标2.确定肥胖时PVAT中Notch信号的升高如何影响其表型和 血管疾病。我们将使用小鼠遗传方法来改变PVAT中的Notch信号，并结合 以高脂饮食喂养ApoE基因缺失小鼠，研究其对PVAT生物学和动脉粥样硬化形成的影响。PVAT 表型将根据棕色、米色或白色脂肪样体的身份进行评估；并通过评估 脂肪因子的产生和炎症。可通过交叉引用更改来识别唯一的凹槽目标 在AIM 1中确定的蛋白质特征。最后，PVAT脂肪细胞前体细胞及其分化能力 会在不同的高脂饮食条件下表现出导致动脉粥样硬化的特点。 具体目标3.评估肥胖过程中Sirt基因Notch调节有助于 PVAT表型的变化及其旁分泌信号对血管壁的影响。我们将在体内利用 使用来自冠状动脉旁路移植手术的人PVAT、肥胖小鼠模型和 Notch活性和代谢状态不同的小鼠分离PVAT的体外研究。